Polychaetes are common in most marine habitats and dominate many infaunal communities. Functional guild classification based on taxonomic identity and morphology has linked community structure to ...ecological function. The functional guilds now include osmotrophic siboglinids as well as sipunculans, echiurans, and myzostomes, which molecular genetic analyses have placed within Annelida. Advances in understanding of encounter mechanisms explicitly relate motility to feeding mode. New analyses of burrowing mechanics explain the prevalence of bilateral symmetry and blur the boundary between surface and subsurface feeding. The dichotomy between microphagous deposit and suspension feeders and macrophagous carnivores, herbivores, and omnivores is further supported by divergent digestive strategies. Deposit feeding appears to be limited largely to worms longer than 1 cm, with juveniles and small worms in general restricted to ingesting highly digestible organic material and larger, rich food items, blurring the macrophage-microphage dichotomy that applies well to larger worms.
Feline infectious peritonitis (FIP) is caused by a mutant biotype of the feline enteric coronavirus. The resulting FIP virus (FIPV) commonly causes central nervous system (CNS) and ocular pathology ...in cases of noneffusive disease. Over 95% of cats with FIP will succumb to disease in days to months after diagnosis despite a variety of historically used treatments. Recently developed antiviral drugs have shown promise in treatment of nonneurological FIP, but data from neurological FIP cases are limited. Four cases of naturally occurring FIP with CNS involvement were treated with the antiviral nucleoside analogue GS‐441524 (5‐10 mg/kg) for at least 12 weeks. Cats were monitored serially with physical, neurologic, and ophthalmic examinations. One cat had serial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis (including feline coronavirus FCoV) titers and FCoV reverse transcriptase RT‐PCR) and serial ocular imaging using Fourier‐domain optical coherence tomography (FD‐OCT) and in vivo confocal microscopy (IVCM). All cats had a positive response to treatment. Three cats are alive off treatment (528, 516, and 354 days after treatment initiation) with normal physical and neurologic examinations. One cat was euthanized 216 days after treatment initiation following relapses after primary and secondary treatment. In 1 case, resolution of disease was defined based on normalization of MRI and CSF findings and resolution of cranial and caudal segment disease with ocular imaging. Treatment with GS‐441524 shows clinical efficacy and may result in clearance and long‐term resolution of neurological FIP. Dosages required for CNS disease may be higher than those used for nonneurological FIP.
Recent studies disagree on whether musicians have an advantage over non-musicians in understanding speech in noise. However, it has been suggested that musicians may be able to use differences in ...fundamental frequency (F0) to better understand target speech in the presence of interfering talkers. Here we studied a relatively large (N = 60) cohort of young adults, equally divided between non-musicians and highly trained musicians, to test whether the musicians were better able to understand speech either in noise or in a two-talker competing speech masker. The target speech and competing speech were presented with either their natural F0 contours or on a monotone F0, and the F0 difference between the target and masker was systematically varied. As expected, speech intelligibility improved with increasing F0 difference between the target and the two-talker masker for both natural and monotone speech. However, no significant intelligibility advantage was observed for musicians over non-musicians in any condition. Although F0 discrimination was significantly better for musicians than for non-musicians, it was not correlated with speech scores. Overall, the results do not support the hypothesis that musical training leads to improved speech intelligibility in complex speech or noise backgrounds.
Existing mouse models of lethal Ebola virus infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever, neither delayed blood coagulation and disseminated intravascular coagulation nor ...death from shock, thus restricting pathogenesis studies to nonhuman primates. Here we show that mice from the Collaborative Cross panel of recombinant inbred mice exhibit distinct disease phenotypes after mouse-adapted Ebola virus infection. Phenotypes range from complete resistance to lethal disease to severe hemorrhagic fever characterized by prolonged coagulation times and 100% mortality. Inflammatory signaling was associated with vascular permeability and endothelial activation, and resistance to lethal infection arose by induction of lymphocyte differentiation and cellular adhesion, probably mediated by the susceptibility allele Tek. These data indicate that genetic background determines susceptibility to Ebola hemorrhagic fever.
A multicenter single-group trial suggests that adjuvant therapy with paclitaxel plus trastuzumab lowers the risk of relapse in women with small HER2-positive breast cancers.
Overexpression of the ...human epidermal growth factor receptor type 2 (HER2) occurs in approximately 15 to 20% of invasive breast cancers and was historically associated with poor clinical outcomes.
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Trastuzumab, a humanized monoclonal antibody that binds HER2, improves the outcomes for patients with HER2-positive breast cancer. Four phase 3 randomized trials involving more than 8000 patients showed that when trastuzumab was administered in combination with or after chemotherapy, the risk of recurrence was decreased by approximately 50% and overall survival improved.
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These trials focused largely on patients with stage II or stage III HER2-positive breast cancers.
Although patients . . .
The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The primary analysis of ...the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN).
In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m
) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer-specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN.
A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism,
, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%).
With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.
Abstract
The dynein motor complex is thought to aid in homolog pairing in many organisms by moving chromosomes within the nuclear periphery to promote and test homologous interactions. This precedes ...synaptonemal complex (SC) formation during homolog synapsis, which stabilizes homolog proximity during recombination. We observed that depletion of the dynein light chain (DLC-1) in Caenorhabditis elegans irreversibly prevents synapsis, causing an increase in off-chromatin formation of SC protein foci with increasing temperature. This requirement for DLC-1 is independent of its function in dynein motors, as SYP protein foci do not form with depletion of other dynein motor components. In contrast to normal SC-related structures, foci formed with DLC-1 depletion are resistant to dissolution with 1,6-hexanediol, similar to aggregates of SC proteins formed in high growth temperatures. Dynein light chains have been shown to act as hub proteins that interact with other proteins through a conserved binding motif. We identified a similar DLC-1 binding motif in the C. elegans SC protein SYP-2, and mutation of the putative motif causes meiosis defects that are exacerbated by elevated temperatures. We propose that DLC-1 acts as a pre-synapsis chaperone-like factor for SYP proteins to help regulate their self-association prior to the signals for SC assembly, a role that is revealed by its increased essentiality at elevated temperatures.
Regulated torpor and unregulated hypothermia are both characterized by substantially reduced body temperature (Tb) and metabolic rate (MR), but they differ physiologically. Although the remarkable, ...medically interesting adaptations accompanying torpor (e.g., tolerance for cold and ischemia, absence of reperfusion injury, and disuse atrophy) often do not apply to hypothermia in homeothermic species such as humans, the terms "torpor" and "hypothermia" are often used interchangeably in the literature. To determine how these states differ functionally and to provide a reliable diagnostic tool for differentiating between these two physiologically distinct states, we examined the interrelations between Tb and MR in a mammal (Sminthopsis macroura) undergoing a bout of torpor with those of the hypothermic response of a similar-sized juvenile rat (Rattus norvegicus). Our data show that under similar thermal conditions, 1) cooling rates differ substantially (approximately fivefold) between the two states; 2) minimum MR is approximately sevenfold higher during hypothermia than during torpor despite a similar Tb; 3) rapid, endogenously fuelled rewarming occurs in torpor but not hypothermia; and 4) the hysteresis between Tb and MR during warming and cooling proceeds in opposite directions in torpor and hypothermia. We thus demonstrate clear diagnostic physiological differences between these two states that can be used experimentally to confirm whether torpor or hypothermia has occurred. Furthermore, the data can clarify the results of studies investigating the ability of physiological or pharmacological agents to induce torpor. Consequently, we recommend using the terms "torpor" and "hypothermia" in ways that are consistent with the underlying regulatory differences between these two physiological states.
The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and ...transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.
BACKGROUND AND PURPOSE—Value-based health care aims to bring together patients and health systems to maximize the ratio of quality over cost. To enable assessment of healthcare value in stroke ...management, an international standard set of patient-centered stroke outcome measures was defined for use in a variety of healthcare settings.
METHODS—A modified Delphi process was implemented with an international expert panel representing patients, advocates, and clinical specialists in stroke outcomes, stroke registers, global health, epidemiology, and rehabilitation to reach consensus on the preferred outcome measures, included populations, and baseline risk adjustment variables.
RESULTS—Patients presenting to a hospital with ischemic stroke or intracerebral hemorrhage were selected as the target population for these recommendations, with the inclusion of transient ischemic attacks optional. Outcome categories recommended for assessment were survival and disease control, acute complications, and patient-reported outcomes. Patient-reported outcomes proposed for assessment at 90 days were pain, mood, feeding, selfcare, mobility, communication, cognitive functioning, social participation, ability to return to usual activities, and health-related quality of life, with mobility, feeding, selfcare, and communication also collected at discharge. One instrument was able to collect most patient-reported subdomains (9/16, 56%). Minimum data collection for risk adjustment included patient demographics, premorbid functioning, stroke type and severity, vascular and systemic risk factors, and specific treatment/care-related factors.
CONCLUSIONS—A consensus stroke measure Standard Set was developed as a simple, pragmatic method to increase the value of stroke care. The set should be validated in practice when used for monitoring and comparisons across different care settings.
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